4.4.6 Other Project Information Component: Project Summary/Abstract This Phase 2 clinical trial will determine if monthly oral vitamin D can reduce the risk of respiratory complications in children with sickle-cell disease. Accumulating evidence indicates that vitamin D, in addition to its role in calcium and bone homeostasis, is a multifunctional regulator of innate and adaptive immune responses and of inflammation that can reduce the risk of respiratory infection and asthma exacerbations in children. Inadequate amounts of vitamin D have been linked to impaired lung function and an increased risk of respiratory infections and asthma atacks. Sickle-cell disease, an orphan disease affecting an estimated 89,000 individuals in the United States, is an inherited red blood cel disorder with acute vaso-occlusive complications and chronic multi-organ damage resulting from microvascular oclusion, hemolysis-induced endothelial dysfunction and vasculopathy. Functional asplenia from sickling-induced infarctions during early childhood impairs immune defenses. Respiratory complications are the leading cause of morbidity and of death in sickle-cell disease. Increased susceptibility to infection and a heightened inflammatory response are critical components of the pathogenesis of lung disease in sickling disorders. Local and national studies have found that most children with sickle-cell disease have very low serum 25-hydroxyvitamin D levels. Vitamin D has potent antimicrobial and immunomodulatory properties that may help prevent respiratory complications in sickle-cell disease. This project is a 2-year controlled, double-blind, randomized Phase 2 clinical trial comparing the efficacy of oral vitamin D3, 100,000 IU (2.5 mg) given once a month, with standard-dose oral vitamin D3, 12,000 IU (0.3 mg) given once a month, in reducing the rate of respiratory events in 80 children and adolescents, 3 to 20 years old, with sickle-cell disease. This monthly dose of oral vitamin D3 has been selected to achieve levels of vitamin D associated with decreased susceptibility to respiratory viral infections and asthma exacerbations but to not exceed levels found among individuals living in a sun-rich environment. This trial has three specific aims: (1) to determine whether monthly oral vitamin D3 (100,000 IU [2.5 mg]), given to children and adolescents with sickle-cell disease, will reduce the rate of respiratory events, defined as respiratory infections, exacerbations of asthma, and episodes of the acute chest syndrome; (2) to evaluate the effects of monthly oral vitamin D3 on pulmonary function, airway hyperreactivity and airway inflammation; and (3) to examine the effects of monthly oral vitamin D3 on immune function, using measures of T-cell effector and regulatory function and of systemic inflammation